Loss of insulin producing cells in the pancreatic islets, the endocrine component of pancreas, referred here as beta cell mass (BCM), leads to an inability to manage blood sugar levels. This results in diabetes mellitus, type 1 (TIDM) or type 2 (T2DM). T1DM, has previously been known as “insulin-dependent diabetes mellitus,” (IDDM) or “juvenile diabetes.” TIDM is a life-long condition in which the pancreas stops making insulin due to loss of BCM from an autoimmune response. Without insulin, the body is not able to use blood sugar for energy. T1DM treatment involves insulin injections, following a diet plan and exercise, and test blood sugar several times a day. TIDM usually begins before the age of 30. T2DM, previously known as “noninsulin-dependent diabetes mellitus” (NIDDM) or “adult-onset diabetes”, is the most common form of diabetes. About 90 to 95 percent of people who have diabetes have T2DM. People with T2DM diabetes produce insulin, but either do not make enough insulin or their bodies do not use the insulin they make. Individuals with T2DM are overweight and may be able to control their condition by losing weight through diet and exercise and may also need to inject insulin or take medicine along with continuing to follow a healthy program of diet and exercise. Although T2DM commonly occurs in adults, an increasing number of children and adolescents who are overweight are also developing T2DM.
Despite rigorous control of blood sugar, the majority of diabetic patients develop serious late-stage complications including retinopathy, nephropathy, neuropathy, microangiopathy and strokes. A long asymptomatic preclinical period characterized by gradual BCM loss precedes clinical T1DM. The duration of the preclinical phase varies substantially because the disease can be diagnosed both in infancy and in older age groups. The highest incidence is reported in children, with an obvious peak in early puberty. Methods to predict the development of clinical T1DM currently rely on the detection of multiple autoantibodies to islet-associated proteins combined with HLA genotyping. Improvement of the power and reliability of methods to predict diabetes would raise the possibility for pharmacological intervention during the preclinical phase and the honeymoon period to either slow down or arrest the ongoing destruction of the remaining β-cells. Currently, the only accepted end-point for drug trials is the clinical diagnosis of T1DM. Despite rigorous control of blood sugar, the majority of diabetic patients develop serious late-stage complications including retinopathy, nephropathy, neuropathy, microangiopathy and strokes. A long asymptomatic preclinical period characterized by gradual BCM loss precedes clinical T1DM. The duration of the preclinical phase varies substantially because the disease can be diagnosed both in infancy and in older age groups. The highest incidence is reported in children, with an obvious peak in early puberty. Methods to predict the development of clinical T1DM currently rely on the detection of multiple autoantibodies to islet-associated proteins combined with HLA genotyping. Improvement of the power and reliability of methods to predict diabetes would raise the possibility for pharmacological intervention during the preclinical phase and the honeymoon period to either slow down or arrest the ongoing destruction of the remaining β-cells. Currently, the only accepted end-point for drug trials is the clinical diagnosis of T1DM.
A non-invasive imaging approach to monitor BCM would enable earlier and better diagnosis/management of both TIDM and T2DM since pancreas is not an ideal organ for biopsy. Several groups have described non-invasive imaging approaches to detect and follow loss of BCM and has been reviewed recently (Souza et al., Cur Med Chem 2006 13:2761). Each of these methods has advantages and disadvantages. For example, bioluminescence imaging using luciferase-expressing mouse or human islets restored euglycemia in NOD-SCID mice and the bioluminescence of the transplanted islets was quantified with a high degree of sensitivity. An early MRI approach tracked the ingress into islets of adoptively transferred lymphocytes pre-labeled with superparamagnetic iron oxide particles (CLIO) and FITC-conjugated Tat-derived peptide. Ex vivo MRI imaging detected the labeled lymphocytes in the islets of NOD-SCID mice but not control C57BL/6J mice. An extension of this method involved pre-labeling CD8+ lymphocytes with nanoparticles of CLIO-NOD-relevant V7 (CLIO-NRP-V7) peptide and transferring them into 8.3-NOD mice, which express a transgenic T cell receptor that recognizes NRP-V7. In vivo MRI imaging detected islet infiltration of the transferred lymphocytes. This MRI method requires pre-labeling of lymphocytes before transfer into recipients, which is a limitation when studying the progression of insulitis and β-cell loss during T1DM. A magnetic resonance imaging (MRI) approach involves the visualization of pancreatic microvasculature changes that accompany insulitis. Injected monocrystalline dextran-coated iron oxide superparamagnetic nanoparticles exit the blood stream at sites of vascular leakage. In NOD mice, MRI revealed accumulation of the magnetic particles in macrophages that infiltrated islets during EAD. Translation of this promising technique into the clinical realm could provide a vital tool for the early detection of insulitis and 1-cell destruction.
Various radiotracer methods are currently underway to study differential pancreatic uptake of 6-deoxy-6-125I-iodo-D-glucose, 3H-monosaccharide D-mannoheptulose, 3H-glibenclamide, 2-14C-alloxan, 11C-acetate and 11C-methionine have been reported. Ex vivo radioimmunoscintigraphy with radio-labeled anti-IC2 monoclonal antibody showed a significant reduction in β-cells in streptozotocin-induced diabetes, but the method has yet to be used in vivo. In a recent PET study, VMAT2 (vesicular monoamine transporter-2) in pancreatic beta cells and in sympathetic nerve terminals that innervate islets and exocrine pancreas, was targeted using the specific radioligand 11C-dihydrotetrabenazine. Serial PET scanning over a 5 week period revealed a 50% loss in β-cell mass that accompanied the progression of EAD in DP-BB/W rats (Souza et al., J Clin Invest 2006 116:1506; Simpson et al., Nucl Med Biol 2006 33:855). Another recent promising study is the use of 18F-FDOPA which was successfully used to diagnose infants with congenital hyperinsulinism (Hardy et al., J Pediatrics 2007 150:140). This ability to diagnose insulin-related disorders is in great need (Sperling J Pediatrics 2007 150:122).
Dopamine D2 receptor (D2R) expression have recently been demonstrated on rodent and human β-cells using isolated islets and beta cell lines (Rubi et al., J Biol Chem 2005 280:36824). D2Rs co-localized with insulin in intracellular granules and quinpirole, a D2R agonist, inhibited glucose-dependent insulin secretion. This report did not ascertain if D2R expression in the pancreas was confined to the endocrine pancreatic islets, or whether it was also present in the exocrine tissues.
We have been involved in developing noninvasive PET diagnostic imaging methods for D2R. A novel dopamine D2/D3 receptor imaging agent fallypride (FIG. 1, labeled with either carbon-11 (20 min half-life) or fluorine-18 (110 min half-life)) has been developed and we have shown its ability to study both the human and nonhuman brain and other peripheral organs (Mukherjee et al., Nucl Med Biol 1995 22:283; Mukherjee et al., Nucl Med Biol 1999 26:519; Mukherjee et al. Synapse 2002 46:170; Mukherjee et al. Bioorganic Medicinal Chem 2004 12:95; Xue et al., J Nucl Med 2004 45:258P).
In one aspect, this application provides novel diagnostic markers for BCM and therefore be useful for evaluating T1DM, T2DM and related disorders of the pancreas or identifying individuals or patients who will develop T1DM, T2DM in the near future.